Device and method for aerosolized delivery of substance to a natural orifice of the body

ABSTRACT

The present invention provides a device for delivering a predetermined volume of a substance, within at least one body cavity of a subject, comprising a predefined volume for containing the predetermined volume of the at least one substance; a delivery end for placement in proximity to the body cavity; the delivery end comprises at least one orifice of diameter D [mm]; a valve mechanically connectable to the container, characterized by at least two configurations: (i) an active configuration in which the valve enables delivery of predetermined amount M sub  of the substance; and, (ii) an inactive configuration, in which the valve prevents delivery of the predetermined amount M sub  of the substance from the container to the body cavity; and a fluid tight chamber configured to contain predetermined volume V gas  of pressurized gas at a predetermined pressure, P gas .

CROSS REFERENCE TO RELATED APPLICATIONS

This Application is a Continuation of U.S. application Ser. No.15/982,630, filed on May 17, 2018 which is a Continuation-in-Part ofU.S. Non-Provisional application Ser. No. 14/733,143 filed on Jun. 8,2015 which claims priority to and the benefit of U.S. ProvisionalApplication Nos. 62/117,986 filed on Feb. 19, 2015 and 62/077,246 filedon Nov. 9, 2014. U.S. application Ser. No. 15/982,630 also claimspriority to and the benefit of U.S. Provisional Application No.62/507,816 filed on May 18, 2017. The contents of the above applicationsare all incorporated by reference as if fully set forth herein in theirentirety.

FIELD OF THE INVENTION

The present invention generally pertains to a system and methods fordelivering aerosolized substance to a natural orifice of the body.

BACKGROUND OF THE INVENTION

Many devices of the prior art focus on a mechanism to allow betteraerosol formation and better dispersion in the nasal cavity. Othermechanisms for better delivery focus on special formulations thatinclude materials and structures to allow better absorption in thetarget tissue.

Each of these strategies has its advantages and disadvantages. Forexample, improvements to the delivery device can improve bringing thematerial to the desired area, but neglect the need to enhance theabsorption of the compound into and through the mucosal layer. On theother hand, improvements to the composition, the formulation or both canimprove absorption into and through the mucosal layer, but may wellneglect the difficulty of delivering a sufficient amount of the materialto the desired tissue.

It is therefore a long felt need to provide a system which can beoptimized for efficient delivery of a substance to a target site, theoptimization neglecting neither the need to bring sufficient material tothe target site, nor the need to ensure adequate absorption into andthrough the mucosal layer.

SUMMARY OF THE INVENTION

This application incorporates herein by reference the contents of U.S.application Ser. No. 15/982,996 in its entirety.

It is an object of the present invention to disclose a single-dosedevice, system, kit and method for delivering aerosolized substance to anatural orifice of the body.

It is another object of the present invention to disclose a unit dosedevice for delivering a predetermined amount M_(sub) of at least onesubstance, within at least one body cavity of a subject, the unit dosedevice comprising: at least one predefined volume sized and shaped forcontaining the predetermined amount M_(sub) of the at least onesubstance; a delivery end for placement in proximity to the body cavity,the delivery end being in fluid communication with the container; thedelivery end comprises at least one orifice of diameter D; at least onevalve mechanically connectable to the container, characterized by atleast two configurations: (i) an active configuration in which the valveenables delivery of predetermined amount M_(sub) of the substance fromthe container to the body cavity via the delivery end; and, (ii) aninactive configuration, in which the valve prevents delivery of thepredetermined amount M_(sub) of the substance from the container to thebody cavity; the valve is reconfigurable from the inactive configurationto the active configuration within a predetermined period of time, dT,in response to activation of the same; and a fluid tight chamberconfigured to contain predetermined volume V_(gas) of pressurized gas ata predetermined pressure, P_(gas); the pressurized gas, once the valveis reconfigured from the inactive configuration to the activeconfiguration, is configured to entrain the substance and deliver thesame via the orifice in the delivery end; wherein the predeterminedamount M_(sub) is no more than 100 μl of a liquid substance pertransition to the active configuration and no more than 190 mm³ of apowder substance per transition to the active configuration.

It is well within the scope of the invention whereat the inactiveconfiguration, gas that was pressurized beforehand and at a remotelocation, is maintained in its container, until activation and spraythereof.

It is another object of the present invention to disclose the unit dosedevice as described above, wherein the unit dose device has aconfiguration selected from a group consisting of configured to delivera single unit dose or configured to deliver two-unit doses.

It is another object of the present invention to disclose the unit dosedevice as described above, wherein the unit dose device configured todeliver a single unit dose delivers no more than 140 mm³ of a powdersubstance per transition to the active configuration.

It is another object of the present invention to disclose the unit dosedevice as described above, wherein the unit dose device is configured todeliver the predetermined amount M_(sub) of the substance and thepredetermined volume V_(gas) of the pressurized gas through the orificeof diameter D in (a) pressure rate of dP_(gas)/dT; (b) volume rate ofdV_(gas)/dT; and (c) amount rate of dM_(sub)/dT; at least one of thefollowing being held true: P_(gas) is in a range of 1 to 10 barg;V_(gas) is in a range of 1 to 50 ml; D is in a range of 0.2 to 6 mm; thepressure velocity dP_(gas)/dT is greater than 0.001 barg/ms; the amountrate dM_(sub)/dT is greater than 0.0001 ml/ms or greater than 0.0001mg/ms; plume of said aerosol by a plume angle θ, said plume angle θsubtending the full width of said plume, said plume angle θ subtendingan angle of less than about 25 θ; the volume rate dV_(gas)/dT is greaterthan 0.001 ml/ms; dT is in a range of 0 to 500 millisecond; and anycombination thereof.

It is another object of the present invention to disclose the unit dosedevice as described above, wherein at least one of the following istrue: the body orifice is a nasal cavity, the mouth, the throat, an ear,the vagina, the rectum, the urethra, and any combination thereofviscosity η of the substance is in a range of 1×10⁻³ poise to 1 poise;DV50 diameter of particles of the substance, after exit from the unitdose device, is less than 200 μm; DV90 diameter of the particles is lessthan 1000 μm; a full width of a plume of aerosol comprising thesubstance and the gas subtends an angle θ of less than 25°; particles inthe plume have velocities in a range of 5 m/s to 50 m/s; the pressurizedgas comprises air, nitrogen, oxygen, carbon dioxide, helium, neon, xenonand any combination thereof; during dispensing of the at least onesubstance, a mixture of the predetermined volume V_(gas) of thepressurized gas with the predetermined amount M_(sub) of the substanceentrained within it forms a plume of aerosol; the aerosol having apredetermined distribution, the distribution being either homogeneous orheterogeneous, the heterogeneous distribution is selected from a groupconsisting of: an arbitrary distribution, a distribution in which thedensity of the at least one substance within the mixture follows apredetermined pattern, and any combination thereof; characteristics ofthe aerosol selected from a group consisting of: particle size, particleshape, particle distribution, and any combination thereof, aredeterminable from characteristics of the unit dose device selected froma group consisting of: the predetermined volume of the pressurized gas,the predetermined volume of the substance, the predetermined pressure ofthe pressurized gas, the predetermined orifice size, and any combinationthereof; at least one the substance is stored under either an inertatmosphere or under vacuum to prevent reactions during storage; adose-response curve is substantially linear for brain concentration ofthe substance when administered nasally via the unit dose device; and adose-response curve for brain concentration having a fit selected from agroup consisting of logarithmic, parabolic, exponential, sigmoid,power-law, and any combination thereof; of the substance whenadministered nasally via the unit dose device.

It is another object of the present invention to disclose the unit dosedevice as described above, wherein the volume of the substance (e.g., adrug) is stored in a container.

It is another object of the present invention to disclose the unit dosedevice as described above, wherein the container is a capsule having amain longitudinal axis, the capsule comprising a number n ofcompartments, the capsule configured to contain the predetermined amountM_(sub) of the at least one substance, the amount M_(sub) of the atleast one substance containable in at least one of the n compartments;at least one of the following being true: the number n of thecompartments is an integer greater than or equal to 1; at least one thecompartment has cross-section with shape selected from a groupconsisting of: wedge shaped, circular, oval, elliptical, polygonal,annular, and any combination thereof; for the number n of compartmentsbeing an integer greater than 1, at least two the compartments havedifferent volumes; for the number n of compartments being an integergreater than 1, at least two the compartments have the same volume; forthe number n of compartments being an integer greater than 1, at leasttwo the compartments have different cross-sectional areas; for thenumber n of compartments being an integer greater than 1, at least twothe compartments have the same cross-sectional area; for the number n ofcompartments being an integer greater than 1, at least two thecompartments contain different substances; for the number n ofcompartments being an integer greater than 1, at least two thecompartments contain the same substance; for the number n ofcompartments being an integer greater than 1, at least two thecompartments are disposed coaxially around the main longitudinal axis ofthe capsule; for the number n of compartments being an integer greaterthan 1, at least two the compartments are disposed sequentially alongthe main longitudinal axis of the capsule; for the number n ofcompartments greater than 1, the plurality of substances mix during thedispensing; and for the number n of compartments greater than 1, theplurality of substances react during the dispensing.

It is another object of the present invention to disclose the unit dosedevice as described above, wherein the container comprises a portfluidly connectable to the exterior of the unit dose device, the portconfigured such that the at least one substance is insertable into thechamber via the port.

It is another object of the present invention to disclose the unit dosedevice as described above, wherein the unit dose device comprises a portcover configured to provide an air-tight closure for the port, the portcover slidable along the unit dose device, rotatable around the unitdose device, rotatable around a hinge on the exterior of the unit dosedevice and any combination thereof.

It is another object of the present invention to disclose a method ofdelivering a predetermined amount M_(sub) of at least one substancewithin at least one body cavity of a subject, comprising: providing aunit dose device comprising: at least one predefined volume sized andshaped for containing the predetermined amount M_(sub) of the at leastone substance; a delivery end in fluid communication with the container;the delivery end comprising at least one orifice of diameter D; at leastone valve mechanically connected to the container, characterized by atleast two configurations: (i) an active configuration in which the valveenables delivery of the predetermined amount M_(sub) of the substancefrom the container to the body cavity via the delivery end; and, (ii) aninactive configuration, in which the valve prevents delivery of thepredetermined amount M_(sub) of the substance from the container to thebody cavity; the valve is reconfigurable from the inactive configurationto the active configuration within a predetermined period of time, dT,in response to activation of the same; and a fluid tight chamberconfigured to contain predetermined volume V_(gas) of pressurized gas ata predetermined pressure, P_(gas); emplacing the substance in thepredefined volume; setting the valve in the inactive configuration;pressurizing the fluid-tight chamber with the gas to the predeterminedpressure; placing the delivery end in proximity to the body cavity;reconfiguring the valve from the inactive configuration to the activeconfiguration thereby entraining the substance in the predeterminedvolume V_(gas) of the pressurized gas; thereby delivering thepredetermined amount M_(sub) of the substance and the predeterminedvolume V_(gas) of the pressurized gas through the orifice of diameter Din a pressure rate of dP_(gas)/dT wherein the predetermined amountM_(sub) is less than 100 μl of a liquid substance and less than 190 mm³of a powder substance.

It is another object of the present invention to disclose the method asdescribed above, additionally comprising a step of selecting aconfiguration for the unit dose device from a group consisting ofconfigured to deliver a single unit dose or configured to delivertwo-unit doses.

It is another object of the present invention to disclose the method asdescribed above, additionally comprising a step of the unit dose deviceconfigured to deliver a single unit dose delivering no more than 140 mm³of a powder substance per transition to the active configuration.

It is another object of the present invention to disclose the method asdescribed above, additionally comprising at least one of the followingsteps: selecting P_(gas) to be in a range of 1 to 10 barg; selectingV_(gas) to be in a range of 1 to 50 ml; selecting D to be in a range of0.2 to 6 mm; selecting the pressure rate to be greater than 0.001barg/ms; selecting the volume rate dM_(sub)/dT to be greater than 0.0001ml/ms or greater than 0.0001 mg/ms; selecting the volume ratedV_(gas)/dT to be greater than 0.001 ml/ms; selecting dT to be in arange of 0 to 500 millisecond and any combination thereof.

It is another object of the present invention to disclose the method asdescribed above, additionally comprising at least one of the followingsteps: selecting the body orifice from a group consisting of a nasalcavity, the mouth, the throat, an ear, the vagina, the rectum, theurethra, and any combination thereof; selecting viscosity η of thesubstance to be in a range of 1×10⁻³ poise to 1 poise; characterizingparticles of the substance in a delivered aerosol, the aerosol a mixtureof the at least one substance and the gas, by a DV50 diameter, the DV50diameter being less than 150 μm; characterizing the particles by a DV90diameter of less than 1000 μm; characterizing a plume of the aerosol bya plume angle θ, the plume angle θ subtending the full width of theplume, the plume angle θ subtending an angle of less than 25°;characterizing velocities of particles in the plume as being in a rangeof 5 m/s to 50 m/s; selecting the gas from a group consisting of: air,nitrogen, oxygen, carbon dioxide, helium, neon, xenon and anycombination thereof, dispensing the at least one substance, and duringthe step of dispensing, forming a plume of aerosol with predetermineddistribution from a mixture of the predetermined volume V_(gas) of thepressurized gas and the predetermined amount M_(sub) entrained withinit; selecting the predetermined distribution from a group consisting of:a homogeneous distribution, a heterogeneous distribution; selecting theheterogeneous distribution from a group consisting of: an arbitrarydistribution, a distribution in which the density of the at least onesubstance within the mixture follows a predetermined pattern, and anycombination thereof; selecting characteristics of the aerosol from agroup consisting of: particle size, particle shape, particledistribution, and any combination thereof, are determinable fromcharacteristics of the unit dose device selected from a group consistingof: the predetermined volume of the pressurized gas, the predeterminedvolume of the substance, the predetermined pressure of the pressurizedgas, the predetermined orifice size, and any combination thereof;storing at least one the substance under either an inert atmosphere orunder vacuum, thereby preventing reactions during storage; andcharacterizing a dose-response curve for brain concentration of thesubstance to be of substantially linear form; and a dose-response curvefor brain concentration having a fit selected from a group consisting oflogarithmic, parabolic, exponential, sigmoid, power-law, and anycombination thereof; of the substance when administered nasally via theunit dose device.

It is another object of the present invention to disclose the method asdescribed above, wherein the volume is a container.

It is another object of the present invention to disclose the method asdescribed above, additionally comprising steps of providing thecontainer comprising a capsule having a main longitudinal axis, thecapsule comprising a number n of compartments, configuring the capsuleto contain the predetermined amount M_(sub) of the at least onesubstance, containing the amount M_(sub) of the substance in at leastone of the n compartments; additionally comprising at least one of thefollowing steps: providing the capsule with n compartments; n is aninteger greater than or equal to 1; selecting a cross-sectional shape ofat least one of the n compartments from a group consisting of: wedgeshaped, circular, oval, elliptical, polygonal, annular, and anycombination thereof; for the number n of compartments being an integergreater than 1, providing at least two of the plurality of thecompartments having different volumes; for the number n of compartmentsbeing an integer greater than 1, providing at least two the compartmentshaving the same volume; for the number n of compartments being aninteger greater than 1, providing at least two the compartments havingdifferent cross-sectional areas; for the number n of compartments beingan integer greater than 1, providing at least two the compartmentshaving the same cross-sectional area; for the number n of compartmentsbeing an integer greater than 1, providing at least two of thecompartments containing different substances; for the number n ofcompartments being an integer greater than 1, providing at least two ofthe compartments containing the same substance; for the number n ofcompartments being an integer greater than 1, disposing the plurality ofcompartments coaxially around the main longitudinal axis of the capsule;for the number n of compartments being an integer greater than 1,disposing the plurality of compartments sequentially along the mainlongitudinal axis of the capsule; for the number n of compartments beingan integer greater than 1, mixing the plurality of substances during thedispensing; and for the number n of compartments being an integergreater than 1, reacting the plurality of substances during thedispensing.

It is another object of the present invention to disclose the method asdescribed above, additionally comprising a step of inserting thepredetermined volume M_(sub) of the at least one substance into thecontainer via a port fluidly connectable to the exterior of the unitdose device.

It is another object of the present invention to disclose the method asdescribed above, additionally comprising a step of providing anair-tight closure for the port, and of moving the port cover relative tothe unit dose device in at least one motion selected from a groupconsisting of: sliding the port cover along the unit dose device,rotating the port cover around the unit dose device, rotating the portcover around a hinge on the exterior of the unit dose device and anycombination thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

The drawings from the priority applications are incorporated byreference. The invention is herein described, by way of example only,with reference to the accompanying drawings, wherein FIGS. 1A-Hillustrate embodiments of nozzles for devices of the present invention;FIGS. 2A-D, 3, 4A-B, 5A-D, 6A-D, 7A-C, 8A-C, 9, 10A-D, 11A-D, 12A-Dillustrate embodiments of devices of the present invention; and FIG.13A-D discloses another embodiment of the invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

This application incorporates herein by reference the contents of U.S.application Ser. No. 15/982,996 in its entirety.

The following description is provided, alongside all chapters of thepresent invention, so as to enable any person skilled in the art to makeuse of the invention and sets forth the best modes contemplated by theinventor of carrying out this invention. Various modifications, however,will remain apparent to those skilled in the art, since the genericprinciples of the present invention have been defined specifically toprovide a device capable of improving the transfer of medicament to apredetermined desired location and to provide a device capable ofimproving the delivery of medicament through the tissue.

In the present invention, a combination of parameters and forces such aspressure, gas/air volume orifice diameter enable the formation ofoptimized aerosol characteristics for both improved delivery of aerosolto the target area (such as the olfactory epithelium in the nasalcavity) and enhanced absorption at that area for better delivery to adesired tissue (such as the brain).

The term ‘μl’ or ‘μm’ hereinafter refers to the unit micro liters.

The term ‘capsule’ or ‘container’ hereinafter refers to a containerconfigured to contain a flowable substance. The term flowable refershereinafter to any liquid, gas, aerosol, powder and any combinationthereof. It should be emphasized that the term capsule can also refer toa predefined volume within the same in which a flowable substance isplaced. In other words, the predefined volume is sized and shaped toenclose a predefined volume of the substance.

The term ‘plurality’ hereinafter refers to an integer greater than orequal to one.

The term ‘olfactory epithelium’ hereinafter refers to a specializedepithelial tissue inside the nasal cavity. The olfactory epithelium liesin the upper top portion of the nasal cavity.

The term ‘substance’ hereinafter refers to any substance capable offlowing. Such a substance can be a granular material, including apowder; a liquid; a gel; a slurry; a suspension; and any combinationthereof. The term ‘substance’ hereinafter refers to any substancecapable of flowing. Such a substance can be a granular material,including a powder; a liquid; a gel; a slurry; a suspension; and anycombination thereof. The term further refers to one or more members of agroup consisting of proteins; stem-cells; cells, organs, portions,extracts, and isolations thereof; macro-molecules; RNA or other genesand proteins-encoding materials; neurotransmitters; receptorantagonists; biologic response modifiers; hormones; Ketamine;commercially available by Lilly (US) Baqsimi product; biologic responsemodifiers; Glucagon; substrates to treat one of eth followings:anaphylaxis, Parkinson, seizures and opioid overdose; epinephrine;atropine; metoclopramide; commercially available Naloxone or Narcanproducts; Esketamine (Spravato); Radicava [edaravone]; Ingrezza[valbenazine]; Austedo [deutetrabenazine]; Ocrevus [ocrelizumab]; Xadago[safinamide]; Spinraza [nusinersen]; Zinbryta [daclizumab]; Nuplazid[pimavanserin]; Aristada [aripiprazole lauroxil]; Vraylar [cariprazine];Rexulti [brexpiprazole]; Aptiom [eslicarbazepine acetate]; Vizamyl[flutemetamol F18 injection]; Brintellix [vortioxetine]; Tecfidera[dimethyl fumarate]; Dotarem [gadoterate meglumine]; Antibody mediatedbrain targeting drug delivery including aducanumab, gantenerumab,bapineuzumab, solanezumab, ofatumumab CD20, BIIB033, LCN2, HMGB 1;insulin; oxytocin; orexin-A; leptin; benzodiazepine i.e. midazolam;naloxone; perillyl alcohol; camptothecin; phytochemicals includingcurcumin and chrysin; nucleotides; olanzapine; risperidone; Venlafaxin;GDF-5; zonisamide; ropinirole; plant-originated andsynthetically-produced terpenes and cannabinoids, including THC and CBD;valproric acid; rivastigmine; estradiol; topiramate or an equivalentpreparation comprising CAS No. 97240-79-4; MFSD2 or MFSD2A orsodium-dependent lysophosphatidylcholine symporter; and any esters,salts, derivatives, mixtures, combinations thereof, with or without acarrier, liposomes, lyophilic or water-miscible solvents, surfactants,cells, cells fractions, at a therapeutically effective concentration.

The term ‘gas’ refers to any fluid that can be readily compressed. Gasesas used herein include, but are not limited to, air, nitrogen, oxygen,carbon dioxide, helium, neon, xenon and any combination thereof. Devicescharged by hand will typically use air as the carrier gas.

The term ‘channel’ hereinafter refers to a passageway allowing passageof a fluid through at least a portion of a mixing mechanism. The channelcan be disposed within a portion of the mixing mechanism, forming aclosed bore; it can be on an exterior of a portion of the mixingmechanism, forming a groove on the portion of the mixing mechanism, andany combination thereof.

The term ‘about’ refers hereinafter to a range of 25% below or above thereferred value.

The term ‘biologic’ or ‘biologic response modifier’ hereinafter refersto material manufactured in or extracted from biological sources such asa genetically engineered protein derived from human genes, or abiologically effective combination of such proteins.

All pressures herein are gauge pressures, relative to atmosphericpressure. Pressure units will be written herein using the standardabbreviation for “gauge’, namely, “g”. For example, atmospheric pressureis 0 barg and a pressure of 1 bar above atmospheric is 1 barg.

The term ‘release time’ refers hereinafter to the time for the drug andcarrier gas to substantially completely exit the device. Typically, therelease time is affected by the activation time and reflects the timefor the device to reconfigure from the inactive configuration to theactive configuration.

The terms ‘the device’, ‘the present device’, ‘the SipNose device’ and‘SipNose’ will be used interchangeably to refer to the device of thepresent invention.

In all of the embodiments of the device shown hereinbelow, identicalnumbers refer to identical functions. All figures shown herein areillustrative and none is to scale.

The present invention teaches a device for delivering a predeterminedamount of a substance, preferably comprising a medication or combinationof medications, into a body orifice of a subject, the orifice comprisingany of the body's natural orifices, including a nostril, the mouth, theear, the throat, the urethra, the vagina, the rectum and any combinationthereof.

In preferred embodiments of the device, the device comprises a deliverymechanism and a medicament capsule, as described hereinbelow. The devicecan apply a broad range of drugs and materials to the nasal cavity forlocal effect, deliver a broad range of drugs and materials through thenasal cavity to the systemic circulation, deliver a broad range of drugsand materials through the nasal cavity to the central nerve system (CNS)the brain, spinal cord and associated nerves, and any combinationthereof.

The drugs to be applied could be, but are not limited to,pharmaceuticals, natural compounds, biologics, hormones, peptides,proteins, viruses, cells, stem cells and any combination thereof.

However, it should be emphasized that the device can be provided aloneas well as in combination with a capsule.

In some cases, the capsule would be provided with a known medicamentwithin the same and in other cases the capsule would be ‘filled’ withthe medicament just before use.

In some embodiments of the present invention, the device operatingcharacteristics and the substance characteristics can be jointlyoptimized to maximize uptake of the substance at the desired site. Inpreferred variants of such embodiments, uptake is further optimized byexploiting synergies between delivery characteristics generated by thedevice and by the formulation or composition of the delivered material

In some embodiments, the substance comprises one or more agents tooptimize delivery through the mucosal membrane by means of mucoadhesiveagent and/or a permeability enhancer agent and/or a particulateformulation in the nano-particle or macro-particle range, and anycombination thereof. In such embodiments, the combination of the deviceand substance enhance the delivery of the active agent to the targetarea (nasal epithelium and more specifically olfactory epithelium) andfrom there to the target tissue (for example the brain).

A non-limiting example is a composition comprising a drug to bedelivered and at least one chemical permeation enhancer (CPE). In apreferred embodiment, the composition contains two or more CPEs which,by using a nasal delivery device, affect in an additive manner or behavesynergistically to increase the permeability of the epithelium, whileproviding an acceptably low level of cytotoxicity to the cells. Theconcentration of the one or more CPEs is selected to provide thegreatest amount of overall potential (OP). Additionally, the CPEs areselected based on the treatment. CPEs that behave primarily bytranscellular transport are preferred for delivering drugs intoepithelial cells. CPEs that behave primarily by paracellular transportare preferred for delivering drugs through epithelial cells. Alsoprovided herein are mucoadhesive agents that enable the extension of theexposure period of the target tissue/mucus membrane to the active agent,for the enhancement of delivery of the active agent to and through themucus membrane.

In contrast to prior-art nasal delivery devices and technologies, thedevices of the present invention can produce a fine aerosol in the nasalcavity or other desired body orifice at the target area and at thelocation of the target tissue instead of producing the aerosol onlywithin the device or immediately after exit from the device. Utilizingthe pressure as a driving force and the air as a carrier allows thematerial to be released from the nozzle as a mixture of aerosol and apre-aerosolized state. The properties of the resultant aerosol aretypically dependent on the properties of the device and of the mediuminto which the device is discharged. The properties of the device whichaffect the aerosol characteristics are the delivery pressure, the volumeof the delivery gas, the characteristics of its orifice and time toactivate.

In some embodiments, the aerosol properties are fairly independent ofthe delivered substance, while, in other embodiments, the pressure,volume, orifice characteristics, and delivered substance properties canbe co-optimized.

In prior-art devices the aerosol is produced in proximity exit of thedevice. Typically, the aerosol comprises a wide “fan” (plume) of aerosoland a low driving force. Therefore, large droplets typically depositvery close to the exit from the device, while smaller droplets tend toquickly contact the walls of the passage, so that deposition istypically predominantly close to the delivery end of the device, withlittle of the substance reaching desired sites deeper in the bodyorifice, such as the middle and superior turbinates of the nose.

In contrast, in the present device, the aerosol is generated within thedevice and the mixture of gas and substance is fully aerosolized beforeit reaches the device exit, thereby making the quality of the aerosolsubstantially independent of the diameter of the exit.

Unlike the device of the present invention, none of the prior-artdevices provide accurate control of all of the delivery parameters,which include dose volume, carrier volume, pressure, and deliveryvelocity.

A further advantage of the device of the present invention (the SipNosedevice) is that, unlike the prior art devices, it can be configured toaccurately deliver large volumes (>100 μl) at high pressure, such thatthe high-velocity aerosol can be as reliably and reproducibly producedfor large volumes as for small.

In some embodiments, including embodiments intended for use inemergencies or daily home use, the device is a single-use device withonly two states, a loaded state (pre-activated state) and an activatedstate. The device is provided in the loaded state; activation of thetrigger mechanism discharges the gas and substance.

In other embodiments, the device is provided in the pre-activated state.The user transforms the device into the loaded state, pressurizing thegas, and activates the trigger mechanism to discharge the gas andsubstance.

Capsules can be single-compartment or multi-compartment.Single-compartment capsules can comprise a flexible silicone tube,preferably sealed at both ends.

Multi-compartment capsules can contain different components of asubstance in the different compartments; at least one compartment cancontain a carrier gas, and any combination thereof.

In some embodiments, there is a single capsule for the carrier gas andthe substance. Some embodiments have separate capsules for substance andgas.

Some embodiments have the gas held in a gas holding chamber. The gasholding chamber can be filled at the time of manufacture or can befilled to the predetermined pressure by a charging mechanism.

Some embodiments have the substance held in a holding chamber. Theholding chamber can be filled at the time of manufacture or can befilled by a filling mechanism such as, but not limited to, a syringe.

It should be emphasized that the present invention refers to both onecompartment capsules as well as multi-compartment capsules.

In FIG. 1, the nozzle (1100) has a tip extension (1110) with a largerdiameter than the nozzle, the tip extension substantially surroundingthe distal end of the nozzle (1100). In the exemplary embodiment of FIG.1, the tip extension (1110) has holes (1112) in it to allow substance toexit laterally from the extension, and the tip (1110) has at least onehole (1113) in its distal end to allow substance to exit longitudinallyfrom the nozzle (1100). FIG. 1 shows an embodiment of a nozzle with atip extension (1110) and an expandable portion (1120). FIGS. 1E and 1Gshow perspective views of the nozzle from the proximal end, while FIGS.1A and 1C show side views of the nozzle (1100). FIGS. 1B and 1D showcross-sections of the nozzle (1100) along the lines AA in FIG. 1A and BBin FIG. 1C, respectively. FIG. 1F shows an enlarged view of the circledregion C in the center of the nozzle in FIG. 1B, while FIG. 1H shows anenlarged view of the circled region D in the center of the nozzle inFIG. 1D.

FIGS. 1A, 1B, 1E and 1F show the nozzle with unexpanded expandableportion, while FIGS. 1C, 1D, 1G and 1H show the nozzle with expandedexpandable portion.

In the exemplary embodiments of FIG. 1, the tip extension and theexpanded medial extension are substantially toroidal; in otherembodiments, they can be substantially spherical, substantially ovoid,substantially ellipsoidal, substantially the frustum of a cone(preferably with a rounded distal edge), substantially conic (preferablywith a rounded distal edge) and any combination thereof.

The nozzle tip and the tip extension (1110) have a number of holes(1112, 1113) which fluidly connect the bore of the nozzle (1100) to theexterior of the device, allowing material to exit from the interior ofthe device. In the exemplary embodiments shown, there is a hole (1113)(not shown in FIG. 1) in the distal end of the nozzle and four holes(1112) in the tip extension (1100). Both the extension and the distalend of the nozzle can have more or fewer holes and, in some embodiments,one or the other can have no holes. The holes (1112) can be regularlyspaced around the periphery of the extension, the holes (1112) can beirregularly spaced around the periphery, the holes (1112) can beconcentrated in a predetermined part of the periphery, and anycombination thereof. Similarly, the holes in the distal end of the tipcan be regularly or irregularly spaced in the tip.

In some embodiments, the extension (1110) can be padded, can comprisesoft material, can comprise flexible material and any combinationthereof.

Extensions, both tip extensions and medial extensions, can have a numberof functions. A non-limiting list of such functions is (1) ensuringproper positioning of the nozzle (1100) in the nasal passages, where theproper position can be the nozzle (1100) centralized in the nasalpassages, the nozzle (1100) touching a predetermined portion of thenasal passages, or the nozzle (1100) closer to a predetermined portionof the nasal passages, (2) sealing the nasal passages so that materialcannot escape therefrom, (3) sealing the nasal passage so that substancedoes not contact undesired portions thereof, (4) sealing the nasalpassage so that substance remains in a predetermined region of the nasalpassage, (5) reducing the discomfort of contact between the nozzle andthe nasal passages, especially in embodiments where the extension isintended to seal against the walls of the nasal passages, by providing asoft and/or flexible contact region and any combination thereof. Properpositioning can be for the purpose of improving delivery of a substanceto a predetermined area, preventing clogging of the holes by nasalsecretions, preventing clogging of the holes by contact with the nasalpassages, mucosa and any combination thereof.

Nozzle extensions, both those that are expanded during the activationprocedure and those that have a predetermined shape and do not expand,can either (1) be attached to the nozzle in a way that they are removedfrom the nasal cavity with the nozzle tip itself, or (2) have the optionof being releasable from the nozzle tip so that they stay in the nasalcavity until they are pulled out by the user or by a caregiver, or anycombination thereof. In embodiments where at least one nozzle extensionremains in a nasal cavity, preferably, the nozzle extension orextensions are removed after a predetermined time, preferably a shorttime.

In some embodiments, the holes (1112) in the nozzle (1100) do not liesubstantially in a plane perpendicular to the main longitudinal axis ofthe nozzle (1100). In such embodiments, the holes (1112) can lie along aline parallel to the main longitudinal axis of the nozzle (1100), alonga line forming a spiral around the nozzle (1100), irregularly in thedistal portion of the nozzle (1100), regularly spaced in the distalportion of the nozzle (1100), and any combination thereof.

Therefore, dispersion of the drug can be substantially from a ringperpendicular to the main longitudinal axis of the nozzle (1100) (holes(1112) around the edge of the extension (1110), from a circleperpendicular to the main longitudinal axis of the nozzle (1100) (holes(1113) in the distal tip of the nozzle (1100), from a line (holes (1112)parallel to the main longitudinal axis of the nozzle (1100) or in aspiral around the main longitudinal axis of the nozzle (1100), or fromat least part of the surface of a volume extending along the side of thenozzle (1100).

In some embodiments, the size of the tip extension (1110) is selected sothat the extension (1110) is in contact with the nasal passagessubstantially along its entire circumference. In such embodiments,material exiting holes (1113) in the distal tip of the nozzle (1100) orholes (1112) on the distal face of the extension (1110) cannot reachregions proximal to the extension (1110) and will reach only regionsdeeper in the nasal passages than the extension (1110). In suchembodiments, the substance will reach the upper parts of the nasalpassages.

Material exiting from holes (1112) in locations where the extension(1110) is in contact with the nasal passages will deposit directly onthe walls of the nasal passages. In such embodiments, deposition is in avery narrow band; the location of the band can be tailored for thematerial of interest.

Material exiting holes (1112) proximal to the region of the extension(1110) in contact with the walls of the nasal passages will be unable toreach locations distal to the region of the extension (1110) in contactwith the walls of the nasal passages and will therefore deposit in thelower parts of the nasal passages.

Returning to FIG. 1, in this embodiment, the expandable portion (1120)surrounds the nozzle (1100). In other embodiments, the expandableportion (1120) can partially surround the nozzle (1100). A singleexpandable portion (1120) or a plurality of expandable portions (1120)can be used. An expandable portion can be on the surface of the nozzleor it can be stored within the nozzle, popping out when it expands. Anexpandable portion can have a predetermined shape when expanded. Theshape of the outward-facing part of an expandable portion can be part ofthe surface of a spheroid, can be part of a cylinder, a part of a cone,or can conform to the shape of a predetermined portion of a nasalpassage. Such shaping can help ensure that, on inflation, the expandableportion or portions gently guide the nozzle so that it rests in theposition with respect to the nasal passages or in the correct portion ofthe nasal passages. It can also reduce the user's discomfort when thedevice is in place or, if detachable from the device, it can seal thenasal passage for a time, before being removed by the user or acaretaker.

The expandable portion (1120) is preferably inflated after insertion ofthe device into the nasal passage. Inflation can be before or at thetime of activation of the device.

FIG. 2A-D shows an embodiment of the device. FIGS. 2A and 2D show theexterior of the device, with FIG. 2A in plain view and FIG. 2D inperspective view, FIG. 2B shows a cross-section along the line A-A inFIG. 2A, and FIG. 2C shows the body (10, 15, 42) separate from themedicine capsule (45) and nosepiece (48).

FIG. 3 shows an exploded view of the device. The device comprises 5 mainsections, a body (1), a capsule section (2), a nosepiece (3), a cover(4) and an activation safety lock (5). The activation safety lockprevents accidental activation of the device and also prevents reuse ofthe device if such is undesirable.

FIG. 4A-B shows an embodiment of the body (10, 15) of a nasal deliverydevice, with FIG. 4B showing the exterior of the body and FIG. 4Ashowing an exploded view. The nosepiece is not shown. The body comprisesa base (10), an air chamber gate (12) with a first gate O-ring (11) atits proximal end and a second gate O-ring (13) at its distal end. Thedistal end of the air chamber gate (12) is covered by a drug containerbase cover (14) which comprises a biocompatible material to ensure thatsubstance that is to contact living tissue only contacts biocompatiblematerial before the contact with living tissue. The compressed gaschamber (15) will fit over the air chamber gate (12), with the firstgate O-ring (11) and the second gate O-ring (13) providing airtightseals before activation so that compressed gas is storable between theair chamber gate (12) and the compressed gas chamber (15). Thecompressed gas chamber (15) is connectable at its distal end with a nosepiece (not shown). The distal portion of the compressed gas chamber (15)comprises activation holders (15C)

FIG. 12A-D shows an embodiment of the body of FIG. 11, as assembled,before activation. FIG. 12A shows the exterior of the body, while. FIG.12B shows a cross-section taken along the line A-A in FIG. 12A. FIG. 12Cis an enlarged view of the circled section B in FIG. 12B, while FIG. 12Dis a perspective view of the body of FIG. 12A. Activation is bycompressing the upper end of the device toward its base, by holding theactivation holders (15C) with the fingers and the bottom of the base(10) with the thumb, and bringing the fingers toward the thumb.

As shown in FIGS. 4A and 4D, in the embodiment of FIGS. 4-6, the base ofthe device forms the activation button (10); to activate, the activationbutton (10) is pressed upward while the compressed gas chamber (gaschamber (15) is held stationary by fingers on the activation holders(15C). The nosepiece is attachable to the compressed gas chamber (15) bymeans of the nose piece connector slot(s) (15C); a protuberance(s) onthe nose piece engages with the nose piece connector slot(s) (15C);permitting fast and easy replacement of the nose piece.

As shown in FIG. 5B, the activation button (10) comprises a gate anchor(10A), a shoulder on which the air chamber gate stopper (12A) restsbefore activation. This to prevent movement of the air chamber gate (12)before activation. The first gate O-ring (11), at the proximal end ofthe gate anchor (10A) and the second gate O-ring (13), at its distalend, provide airtight seals before activation so that compressed gas isstorable between the air chamber gate (12) and the compressed gaschamber (15). The distal end of the air chamber gate (12) is covered bya drug container base cover (14) which comprises a biocompatiblematerial to ensure that substance that is to contact living tissue onlycontacts biocompatible material before the contact with living tissue.The compressed gas chamber (15) is connectable at its distal end with anose piece (not shown) by means of the nose piece connector slot (15B).

FIG. 5C, the enlargement of the area within the circle B of FIG. 5B,clearly shows the gate anchor (10A), with the air chamber gate stopper(12A) resting on it.

FIG. 6A-D shows an embodiment of the body of FIG. 4, as assembled, afteractivation. FIG. 6A shows the exterior of the body, while. FIG. 6B showsa cross-section taken along the line A-A in FIG. 6A. FIG. 6C is anenlarged view of the circled section B in FIG. 6B, while FIG. 6D is anenlarged view of the circled section C in FIG. 6B. Activation is bycompressing the upper end of the device toward its base, by holding theactivation holders (15C) with the fingers and the bottom of the base(10) with the thumb, and bringing the fingers toward the thumb.

As shown in FIGS. 6A and 6D, in the embodiment of FIGS. 5-6, the base ofthe device forms the activation button (10), to activate, the activationbutton (10) is pressed upward while the compressed gas chamber (gaschamber (15) is held stationary by fingers on the activation holders(30). The nosepiece is attachable to the compressed gas chamber (15) bymeans of the nose piece connector slot(s) (15B); a protuberance(s) onthe nose piece engages with the nose piece connector slot(s) (15B),permitting fast and easy replacement of the nose piece.

As shown in FIG. 6B, the activation button (10) comprises a gate anchor(10A), a shoulder on which the air chamber gate stopper (12A) restedbefore activation. During activation, the air chamber gate stopper (12A)is pressed inwards, so that the air chamber gate (12) moves proximally,opening up a gap (17) between the air chamber gate (12) and the distalend of the compressed gas chamber (15), allowing the gas (16) to exitthe compressed gas chamber (15) through the gap, and to enter thenosepiece and forma an aerosol with the substance. The first gate O-ring(11), at the proximal end of the gate anchor (10A) still provide anairtight seal after activation, but the second gate O-ring (13), at itsdistal end, so that compressed gas is storable between the air chambergate (12) and the compressed gas chamber (15) is no longer in contactwith the compressed gas chamber (15). The distal end of the air chambergate (12) is covered by a drug container base cover (14) which comprisesa biocompatible material to ensure that substance that is to contactliving tissue only contacts biocompatible material before the contactwith living tissue. The compressed gas chamber (15) is connectable atits distal end with a nose piece (not shown) by means of the nose piececonnector slot (15B).

FIG. 6C, the enlargement of the area within the circle B of FIG. 6B,clearly shows the gate anchor (10A), with the air chamber gate stopper(12A) no longer in contact with it, but is resting near the base of theactivation button.

FIG. 6D, the enlargement of the area within the circle C of FIG. 6B,clearly shows the distal end of the air chamber gate (12), the drugcontainer base cover (14), the second gate O-ring (13) and the gap (17,FIG. 6B) permitting air to escape (arrow, 15D) from the compressed gaschamber into the intermediate space and then to the nose piece (notshown).

The device also comprises a latching mechanism (10A, 12A) to preventre-use. The latching mechanism (10A, 12A) comprises an air chamber gatestopper (12A), which is an extension downward of the air chamber gate(12).

Before use (FIG. 6C), the air chamber gate stopper (12A) sits above acatch (10A). During activation, the sloped portion of the outer edge ofthe air chamber gate stopper (12A) slides down past the catch (10A).After the body has been fully compressed (FIG. 7C), a shoulder on theair chamber gate stopper (12A) rests underneath a shoulder 15A on thecatch (10A), preventing the activation button (10) from movingproximally relative to the compressed gas chamber (15) and expanding thebody.

FIG. 7A-C shows an embodiment of the device with the primary drugcontainer in the nose piece cover. The medicament or substance isdelivered from the primary drug container to a secondary drug volume inthe nose piece. The nose piece cover can then be removed and the deviceactivated to aerosolize and deliver the drug.

FIG. 7A shows the exterior of the device. It comprises an activationbutton (10), a compressed gas chamber (15), and a nosepiece (not shown)protected by a nose piece cover (20). In the distal portion of the nosepiece cover (20) is a primary drug container (not shown) in a drugcontainer housing (21). The drug container housing is slidable relativeto the nose piece cover (20). The embodiment also comprises an indicatorwindow (22) to determine the quantity of drug remaining in the primarydrug container and a safety lock (23).

FIG. 7B shows a cross-section of the device, taken along the line A-A inFIG. 7A. The base and aerosol generation and delivery mechanism aresimilar to those disclosed above in FIGS. 5-6. The device comprises anose piece (28) with an integral drug volume (29) in its proximalportion. The deliverable substance is stored in a primary drug container(24) in the distal portion of the nose piece cover (20). The primarydrug container (24) is sealed at its proximal end by a plunger stopper(25). A loading needle (26) is fixed to the nose piece cover (20), witha needle adaptor (27) to guide the loading needle's (26) proximal end sothat the proximal end of the needle adaptor (27) passes through theorifice at the tip of the nose piece (28). As shown in FIG. 7B, unlessdrug is being loaded into the integral drug volume (29), the needle doesnot pierce the plunger stopper (25) and the primary drug container (24)remains sealed.

FIG. 7C shows a perspective view of the device. The drug containerhousing (21) can be seen, as well as the nose piece cover (20), whichterminates at its proximal end in a safety lock (23) to prevent unwantedactivation of the device. Movement of the drug container housing (21)relative to the nose piece cover (20) is controlled by a volume scale(30), in this embodiment a ratchet comprising a toothed rack (21A) onthe drug container housing (21) and a pin (20A) on the nose piece cover(20). When the nose piece cover (20) is pressed downward relative to thedrug container housing (21), the distance traveled and, therefore, theamount of drug to be dispensed, is controllable by the volume scale(30); each “click” will dispense a predetermined volume of the drug.

FIG. 8A-C shows the embodiment of the device of FIG. 7 during loading ofthe drug into the integral drug volume (29) from the primary drugcontainer (24).

FIG. 8A shows the exterior of the device. It comprises an activationbutton (10), a compressed gas chamber (15), and a nosepiece (not shown)protected by a nose piece cover (20). In the distal portion of the nosepiece cover (20) is a primary drug container (not shown) in a drugcontainer housing (21). The drug container housing is slidable relativeto the nose piece cover (20). The embodiment also comprises an indicatorwindow (22) to determine the quantity of drug remaining in the primarydrug container and a safety lock (23). The volume scale (30), here aratchet, allows adjustment of the size of the dose.

FIG. 8B shows a cross-section of the device, taken along the line B-B inFIG. 8A. The base and aerosol generation and delivery mechanism aresimilar to those disclosed above in FIGS. 5-6. As shown in FIG. 8B, adrug or medicament (24A) is being loaded from the primary drug containerinto the integral drug volume (29). Loading is activated by pressing theprimary drug container (24) proximally. It then slides along the nosepiece (28). The loading needle (26) is steadied by the needle adaptor(27). Pressing the primary drug container (24) proximally forces theloading needle (26) through the plunger stopper (25) and into theprimary drug container (24). Drug (24A) can then flow through theloading needle (26) into the integral drug volume (29). Releasing theprimary drug container (24) will cause it to move distally and removethe loading needle (26) from the plunger stopper (25). The nose piececover (20) can then be removed and a dose of the drug can beadministered.

FIG. 8C shows a perspective view of the device. The drug containerhousing (21) can be seen, as well as the nose piece cover (20), whichterminates at its proximal end in a safety lock (23) to prevent unwantedactivation of the device. Movement of the drug container housing (21)relative to the nose piece cover (20) is controlled by the volume scale(30), in this embodiment a ratchet comprising a toothed rack (21A) onthe drug container housing (21) and a pin (20A) on the nose piece cover(20). When the nose piece cover (20) is pressed downward relative to thedrug container housing (21), the distance traveled and, therefore, theamount of drug to be dispensed, is controllable by the volume scale(30); each “click” will dispense a predetermined volume of the drug.

FIG. 9 illustrates removal of the nose piece cover or medicine chamber(5) from an aerosol delivery device (1) by pulling (arrow) the medicinechamber (5) away from the aerosol delivery device (9), FIG. 10A-Dillustrates a device with a replaceable nose piece preloaded with asingle dose of a medicament. The medicament can comprise one or moresubstances, as disclosed above. The device further comprises a nosepiece cover with a removable top. FIGS. 10A and 10D show the exterior ofthe device with the nose piece cover in place, with FIG. 10A showing itfrom the side and FIG. 10C showing a perspective view. FIG. 10B shows across section taken along the line A-A in FIG. 10A and FIG. 17C providesa partially exploded view.

FIGS. 10A and 10D show an activation button (10) and compressed gaschamber (15), as disclosed above. The nose piece cover (40) has aremovable orifice closure (41) at its distal end.

FIG. 10B shows a cross-section of the device. The nose piece cover (40)has a reversibly removable nose piece orifice cover (41). The nose piece(42), which comprises an integral drug volume (43), has, at its distalend, a nose piece cover pin (41A) to protect the distal end of the nosepiece. The nose piece (42) is reversibly connectable to the compressedgas chamber (15) by means of a nose piece connecting pin (42A) whichslots into a connector slot (15B, FIG. 10C) at the distal end of thecompressed gas chamber (15)

FIG. 10C shows a partially-exploded view of the device. The nose piece(42) is reversibly connectable to the compressed gas chamber (15) bymeans of a nose piece connecting pin (42A) which slots into a connectorslot (15B) at the distal end of the compressed gas chamber (15). Theactivation button (10) is shown at the proximal end of the compressedgas chamber (15). The removable orifice closure (41) is shown separatedfrom the nose piece cover (40). By this means, only the removableorifice closure (41) needs to be removed to replace a nose piece (28);there is no need to remove the entire nose piece cover (40). The safetylock (2A) to prevent accidental activation of the device is also shown.

FIG. 11A-D illustrates a device which can be loaded with a medicament,drug or substance via a syringe. FIGS. 11A and 11D show the exterior ofthe device, FIG. 11A from the side and FIG. 11D from an angle. FIG. 11Bshows a cross section taken along the line A-A in FIG. 11A and FIG. 11Cshows the loading needle.

As shown in FIG. 11A, the device comprises an activation button (10) andcompressed gas chamber, as disclosed above. The nose piece cover (40)comprises a drug loading adaptor (45) and a reversibly removable drugloading adaptor cap (46) at its distal end. In the embodiment shown, thedrug loading adaptor cap (46) is attached to the nose piece cover (40)by an integral flexible strip (46A), to prevent the drug loading adaptorcap (46) from getting lost.

As shown in FIG. 11B, a drug loading needle (47) is held firmly withinthe drug loading adaptor (45). The drug loading needle (47) extends fromthe top of the nose piece cover (40) through the distal end of the nosepiece (42) to a drug storage volume near the proximal end of the nosepiece (42). The distal portion of the drug loading needle (47) isconfigured by means of shape and size to accept the delivery end of asyringe (not shown). During storage and transport, the drug loadingneedle (47) is retained firmly in place with its distal portion helpfirmly between the closed drug loading adaptor cap (46) and the distaltip of the nose piece (42).

FIG. 18C shows the drug loading adaptor (45) with the drug loadingneedle (47) extending proximally therefrom.

FIG. 11D shows the nose piece cover (40), the drug loading adaptor cap(46) and the drug delivery device with activation button (10).

FIG. 12A-D shows the device of FIG. 11A-D with a syringe in place. Thesyringe can be a proprietary syringe, with a tip matched in shape andsize to the opening in the distal portion of the drug loading needle(47) or it can be a commercial syringe with a tip that fits into theopening in the distal portion of the drug loading needle (47).

FIG. 12A shows a side view of the device with a loading syringe (48) inplace. The drug loading adaptor cap (46) is open and the tip (not shown)of the loading syringe (48) is resting in the distal portion of the drugloading adaptor (45) and nose piece cover (40), with the nose piececover in communication with the activation button (10) and compressedgas chamber (15) of the delivery device.

FIG. 12B shows a cross-section of the set-up of FIG. 12A, taken alongthe line A-A. The loading syringe (48) is resting in the distal portionof the drug loading needle (47). The drug (49) is contained within theloading syringe (48); compression (arrow) of the loading syringe willforce the drug out of the loading syringe (48). The proximal portion ofthe drug loading needle (47) passes through the nose piece (42). Thenose piece (42) is attached, either reversibly or fixedly, to theactivation button (10) and compressed gas chamber (15) of the deliverydevice.

FIG. 12C-D shows how a loading syringe (48), in place in a drug loadingadaptor (45), is connectable to a drug delivery device, comprising nosepiece (42), compressed gas chamber (15) and activation button (10). FIG.19C shows the loading syringe (48) in place in a drug loading adaptor(45), with the drug loading adaptor (45) in position to be attached tothe delivery device. FIG. 12D shows the loading syringe (48) and drugloading adaptor (45), with the drug loading adaptor cap (46) open,attached to the compressed gas chamber (15) and activation button (10)of the delivery device.

Both UD and BD devices are configured to provide delivery of either apowder or a liquid, with accurate dosing and without need for priming.They are configured to be actuated by a single hand and can be used inany position; for example, a device does not need to be held upright.

The maximum dose for a liquid is 100 μl for a unit dose and 2λ100 μl fortwo doses. The maximum dose for a powder is 140 mm³ for a unit dose and190 mm³ per chamber for two doses.

The unit dose devices are configured for use with therapies where asmall and very precise amount of an active drug formulation is requiredin a single nasal or sub-lingual shot. If the required dose is largerthan about 100 μl or when a single dose into each nostril is desired,two-dose device is used.

FIG. 13A-D discloses another embodiment of the invention, especiallyshowing plunger stopper(s) (25), drug (24A) and container (25).

In preferred embodiments, the device comprises a protective cover,removable before use.

In some embodiments, the device is reusable. In other embodiments, itcomprises a safety device/use indicator that must be removed orotherwise damaged before use, so that it is clear that the device hasbeen used and, preferably, prevents re-use of the device.

1. A unit dose device for delivering a predetermined amount M_(sub) ofat least one substance, within at least one body cavity of a subject,said unit dose device comprising: a. at least one predefined volumesized and shaped for containing said predetermined amount M_(sub) ofsaid at least one substance; b. a delivery end for placement inproximity to said body cavity, said delivery end being in fluidcommunication with said container; said delivery end comprises at leastone orifice of diameter D; c. at least one valve mechanicallyconnectable to said container, characterized by at least twoconfigurations: (i) an active configuration in which said valve enablesdelivery of predetermined amount M_(sub) of said substance from saidcontainer to said body cavity via said delivery end; and, (ii) aninactive configuration, in which said valve prevents delivery of saidpredetermined amount M_(sub) of said substance from said container tosaid body cavity; said valve is configurable from said inactiveconfiguration to said active configuration within a predetermined periodof time, dT, in response to activation of the same; and d. a fluid tightchamber configured to contain predetermined volume V_(gas) ofpressurized gas at a predetermined pressure, P_(gas); said pressurizedgas, once said valve is reconfigured from said inactive configuration tosaid active configuration, is configured to entrain said substance anddeliver the same via said orifice in said delivery end; wherein saidpredetermined amount M_(sub) is no more than 100 μl of a liquidsubstance per transition to the active configuration and no more than190 mm³ of a powder substance per transition to the activeconfiguration.
 2. The unit dose device of claim 1, wherein said unitdose device has a configuration selected from a group consisting ofconfigured to deliver a single unit dose or configured to delivertwo-unit doses.
 3. The unit dose device of claim 1, wherein saidinactive configuration, gas that was pressurized beforehand and at aremote location is maintained in its container until activation.
 4. Theunit dose device of claim 2, wherein said unit dose device configured todeliver a single unit dose delivers no more than 140 mm³ of a powdersubstance per transition to the active configuration.
 5. The unit dosedevice of claim 1, wherein said unit dose device is configured todeliver said predetermined amount M_(sub) of said substance and saidpredetermined volume V_(gas) of said pressurized gas through saidorifice of diameter D in (a) pressure rate of dP_(gas)/dT; (b) volumerate of dV_(gas)/dT; and (c) amount rate of dM_(sub)/dT; at least one ofthe following being held true: a. P_(gas) is in a range of 1 to 10 barg;b. V_(gas) is in a range of 1 to 50 ml; c. D is in a range of 0.2 to 6mm; d. said pressure velocity dP_(gas)/dT is greater than 0.001 barg/ms;e. said amount rate dM_(sub)/dT is greater than 0.0001 ml/ms or greaterthan 0.0001 mg/ms; f. said volume rate dV_(gas)/dT is greater than 0.001ml/ms; g. plume of said aerosol by a plume angle θ, said plume angle θsubtending the full width of said plume, said plume angle θ subtendingan angle of less than about 25 θ; h. dT is in a range of 0 to 500millisecond; and i. any combination thereof.
 6. The unit dose device ofclaim 1, wherein at least one of the following is true: a. said bodyorifice is a nasal cavity, the mouth, the throat, an ear, the vagina,the rectum, the urethra, and any combination thereof b. viscosity η ofsaid substance is in a range of 1×10⁻³ poise to 1 poise; c. DV50diameter of particles of said substance, after exit from said unit dosedevice, is less than 100 μm; d. DV90 diameter of said particles is lessthan 1000 μm; e. a full width of a plume of aerosol comprising saidsubstance and said gas subtends an angle θ of less than 25°; f.particles in said plume have velocities in a range of 5 m/s to 50 m/s;g. said pressurized gas comprises air, nitrogen, oxygen, carbon dioxide,helium, neon, xenon and any combination thereof; h. during dispensing ofsaid at least one substance, a mixture of said predetermined volumeV_(gas) of said pressurized gas with said predetermined amount M_(sub)of said substance entrained within it forms a plume of aerosol; saidaerosol having a predetermined distribution, said distribution beingeither homogeneous or heterogeneous, said heterogeneous distribution isselected from a group consisting of: an arbitrary distribution, adistribution in which the density of said at least one substance withinsaid mixture follows a predetermined pattern, and any combinationthereof; characteristics of said aerosol selected from a groupconsisting of: particle size, particle shape, particle distribution, andany combination thereof, are determinable from characteristics of saidunit dose device selected from a group consisting of: said predeterminedvolume of said pressurized gas, said predetermined volume of saidsubstance, said predetermined pressure of said pressurized gas, saidpredetermined orifice size, and any combination thereof; i. at least onesaid substance is stored under either an inert atmosphere or undervacuum to prevent reactions during storage; j. a dose-response curve issubstantially linear for brain concentration of said substance whenadministered nasally via said unit dose device; and k. a dose-responsecurve for brain concentration having a fit selected from a groupconsisting of logarithmic, parabolic, exponential, sigmoid, power-law,and any combination thereof; of said substance when administered nasallyvia said unit dose device.
 7. The unit dose device of claim 1, whereinsaid volume is stored in a container.
 8. The unit dose device of claim5, wherein said container is a capsule having a main longitudinal axis,said capsule comprising a number n of compartments, said capsuleconfigured to contain said predetermined amount M_(sub) of said at leastone substance, said amount M_(sub) of said at least one substancecontainable in at least one of said n compartments; at least one of thefollowing being true: a. the number n of said compartments is an integergreater than or equal to 1; at least one said compartment hascross-section with shape selected from a group consisting of: wedgeshaped, circular, oval, elliptical, polygonal, annular, and anycombination thereof; b. for said number n of compartments being aninteger greater than 1, at least two said compartments have differentvolumes; c. for said number n of compartments being an integer greaterthan 1, at least two said compartments have the same volume; d. for saidnumber n of compartments being an integer greater than 1, at least twosaid compartments have different cross-sectional areas; e. for saidnumber n of compartments being an integer greater than 1, at least twosaid compartments have the same cross-sectional area; f. for said numbern of compartments being an integer greater than 1, at least two saidcompartments contain different substances; g. for said number n ofcompartments being an integer greater than 1, at least two saidcompartments contain the same substance; h. for said number n ofcompartments being an integer greater than 1, at least two saidcompartments are disposed coaxially around said main longitudinal axisof said capsule; i. for said number n of compartments being an integergreater than 1, at least two said compartments are disposed sequentiallyalong said main longitudinal axis of said capsule; j. for said number nof compartments greater than 1, said plurality of substances mix duringsaid dispensing; and k. for said number n of compartments greater than1, said plurality of substances react during said dispensing.
 9. Theunit dose device of claim 1, wherein said container comprises a portfluidly connectable to the exterior of said unit dose device, said portconfigured such that said at least one substance is insertable into saidchamber via said port.
 10. The unit dose device of claim 5, wherein saidunit dose device comprises a port cover configured to provide anair-tight closure for said port, said port cover slidable along saidunit dose device, rotatable around said unit dose device, rotatablearound a hinge on the exterior of said unit dose device and anycombination thereof.
 11. A method of delivering a predetermined amountM_(sub) of at least one substance within at least one body cavity of asubject, comprising: a. providing a unit dose device comprising: i. atleast one predefined volume sized and shaped for containing saidpredetermined amount M_(sub) of said at least one substance; ii. adelivery end in fluid communication with said container; said deliveryend comprising at least one orifice of diameter D; iii. at least onevalve mechanically connected to said container, characterized by atleast two configurations: (i) an active configuration in which saidvalve enables delivery of said predetermined amount M_(sub) of saidsubstance from said container to said body cavity via said delivery end;and, (ii) an inactive configuration, in which said valve preventsdelivery of said predetermined amount M_(sub) of said substance fromsaid container to said body cavity; said valve is reconfigurable fromsaid inactive configuration to said active configuration within apredetermined period of time, dT, in response to activation of the same;and iv. a fluid tight chamber configured to contain predetermined volumeV_(gas) of pressurized gas at a predetermined pressure, P_(gas); b.emplacing said substance in said predefined volume; c. setting saidvalve in said inactive configuration; d. pressurizing said fluid-tightchamber with said gas to said predetermined pressure; e. placing saiddelivery end in proximity to said body cavity; f. reconfiguring saidvalve from said inactive configuration to said active configurationthereby entraining said substance in said predetermined volume V_(gas)of said pressurized gas; thereby g. delivering said predetermined amountM_(sub) of said substance and said predetermined volume V_(gas) of saidpressurized gas through said orifice of diameter D in a pressure rate ofdP_(gas)/dT; wherein said predetermined amount M_(sub) is less than 100μl of a liquid substance and less than 190 mm³ of a powder substance.12. The method of claim 11, additionally comprising a step of selectinga configuration for said unit dose device from a group consisting ofconfigured to deliver a single unit dose or configured to delivertwo-unit doses.
 13. The method of claim 11, additionally comprising astep of said unit dose device configured to deliver a single unit dosedelivering no more than 140 mm³ of a powder substance per transition tothe active configuration.
 14. The method of claim 11, additionallycomprising at least one of the following steps: a. selecting P_(gas) tobe in a range of 1 to 10 barg; b. selecting V_(gas) to be in a range of1 to 50 ml; c. selecting D to be in a range of 0.2 to 6 mm; d. selectingsaid pressure rate to be greater than 0.001 barg/ms; e. selecting saidvolume rate dM_(sub)/dT to be greater than 0.0001 ml/ms or greater than0.0001 mg/ms; f. selecting said volume rate dV_(gas)/dT to be greaterthan 0.001 ml/ms; g. selecting dT to be in a range of 0 to 500millisecond and h. any combination thereof.
 15. The method of claim 11,additionally comprising at least one of the following steps: a.selecting said body orifice from a group consisting of a nasal cavity,the mouth, the throat, an ear, the vagina, the rectum, the urethra, andany combination thereof; b. selecting viscosity η of said substance tobe in a range of 1×10⁻³ poise to 1 poise; c. characterizing particles ofsaid substance in a delivered aerosol, said aerosol a mixture of said atleast one substance and said gas, by a DV50 diameter, said DV50 diameterbeing less than 150 μm; d. characterizing said particles by a DV90diameter of less than 1000 μm; e. characterizing a plume of said aerosolby a plume angle θ, said plume angle θ subtending the full width of saidplume, said plume angle θ subtending an angle of less than 25°; f.characterizing velocities of particles in said plume as being in a rangeof 5 m/s to 50 m/s; g. selecting said gas from a group consisting of:air, nitrogen, oxygen, carbon dioxide, helium, neon, xenon and anycombination thereof; h. dispensing said at least one substance, andduring said step of dispensing, forming a plume of aerosol withpredetermined distribution from a mixture of said predetermined volumeV_(gas) of said pressurized gas and said predetermined amount M_(sub)entrained within it; selecting said predetermined distribution from agroup consisting of: a homogeneous distribution, a heterogeneousdistribution; selecting said heterogeneous distribution from a groupconsisting of: an arbitrary distribution, a distribution in which thedensity of said at least one substance within said mixture follows apredetermined pattern, and any combination thereof; selectingcharacteristics of said aerosol from a group consisting of: particlesize, particle shape, particle distribution, and any combinationthereof, are determinable from characteristics of said unit dose deviceselected from a group consisting of: said predetermined volume of saidpressurized gas, said predetermined volume of said substance, saidpredetermined pressure of said pressurized gas, said predeterminedorifice size, and any combination thereof; i. storing at least one saidsubstance under either an inert atmosphere or under vacuum, therebypreventing reactions during storage; and j. characterizing adose-response curve for brain concentration of said substance to be ofsubstantially linear form; and k. a dose-response curve for brainconcentration having a fit selected from a group consisting oflogarithmic, parabolic, exponential, sigmoid, power-law, and anycombination thereof; of said substance when administered nasally viasaid unit dose device.
 16. The method of claim 11, wherein said volumeis a container.
 17. The method of claim 16, additionally comprisingsteps of providing said container comprising a capsule having a mainlongitudinal axis, said capsule comprising a number n of compartments,configuring said capsule to contain said predetermined amount M_(sub) ofsaid at least one substance, containing said amount M_(sub) of saidsubstance in at least one of said n compartments; additionallycomprising at least one of the following steps: a. providing saidcapsule with n compartments; n is an integer greater than or equal to 1;b. selecting a cross-sectional shape of at least one of said ncompartments from a group consisting of: wedge shaped, circular, oval,elliptical, polygonal, annular, and any combination thereof; c. for saidnumber n of compartments being an integer greater than 1, providing atleast two of said plurality of said compartments having differentvolumes; d. for said number n of compartments being an integer greaterthan 1, providing at least two said compartments having the same volume;e. for said number n of compartments being an integer greater than 1,providing at least two said compartments having differentcross-sectional areas; f. for said number n of compartments being aninteger greater than 1, providing at least two said compartments havingthe same cross-sectional area; g. for said number n of compartmentsbeing an integer greater than 1, providing at least two of saidcompartments containing different substances; h. for said number n ofcompartments being an integer greater than 1, providing at least two ofsaid compartments containing the same substance; i. for said number n ofcompartments being an integer greater than 1, disposing said pluralityof compartments coaxially around said main longitudinal axis of saidcapsule; j. for said number n of compartments being an integer greaterthan 1, disposing said plurality of compartments sequentially along saidmain longitudinal axis of said capsule; k. for said number n ofcompartments being an integer greater than 1, mixing said plurality ofsubstances during said dispensing; and l. for said number n ofcompartments being an integer greater than 1, reacting said plurality ofsubstances during said dispensing.
 18. The method of claim 11,additionally comprising a step of inserting said predetermined volumeM_(sub) of said at least one substance into said container via a portfluidly connectable to the exterior of said unit dose device.
 19. Themethod of claim 18, additionally comprising a step of providing anair-tight closure for said port, and of moving said port cover relativeto said unit dose device in at least one motion selected from a groupconsisting of: sliding said port cover along said unit dose device,rotating said port cover around said unit dose device, rotating saidport cover around a hinge on the exterior of said unit dose device andany combination thereof.